Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical beta-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins were earlier regarded as potent ocular hypertensives; however, evidence accumulated in the last two decades shows that some prostaglandins are highly effective ocular hypotensive agents and are ideally suited for the long-term medical management of glaucoma. (See, for example, Starr, M. S. Exp. Eye Res. 1971, 11, pp. 170-177; Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla. CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505). Such prostaglandins include PGF2α, PGF1α, PGE2, and certain lipid-soluble esters, such as C1 to C5 alkyl esters, e.g., 1-isopropyl ester, of such compounds.
Other uses of bimatoprost include use in hair growth, including scalp hair, eyelashes, and eyebrows. Bimatoprost has also shown promise in localized fat reduction and inhibition of adipocyte differentiation.
Prostaglandins tend generally to occur in the form of oils or gums. Solid forms of some prostaglandins are known in the art. The solid forms may be prone to form change upon solid state manufacturing processes, such as granulation, tablet compression and hot melt extrusion. For example, a solid form of a prostaglandin may take the form of an oil or gum during or after a granulation, tablet compression, or extrusion step.
It is known that many drug compounds exist in two or more crystalline forms, referred to as polymorphs. These polymorphs of the same molecule have identical chemical properties but may exhibit different physical properties, such as melting point, solubility, hardness, etc.
Bimatoprost is known to occur in the solid form. US 2009/0163596 discloses bimatoprost crystalline Form I having a characteristic melting point range of 62-64° C. WO 2011/063276 A1 and U.S. Pat. No. 8,629,185 B2 disclose crystalline bimatoprost polymorph II having an endothermic melting onset at about 70.9° C. and a peak at 74.5° C. in its DSC profile. WO 2012/164324 A1 discloses bimatoprost crystal Form II with a melting point range of 72-78° C. U.S. patent application Ser. No. 14/136,914 discloses crystalline forms of bimatoprost acid, with melting temperatures of 64.2° C. (crystalline Form 1) and 66.4° C. (crystalline Form 2), respectively. U.S. patent application Ser. No. 14/136,914 also discloses that some bimatoprost polymorphs convert to an amorphous material after hot melt extrusion.
Preparation of amino acid salts of prostaglandin free acids are reported by DeLong et al. (see US 2010/0105775 A1). DeLong et al. teach that suitably, the salts have a melting point of at least about 35° C., or at least about 50° C.
When a drug compound exists in two or more crystalline forms, or polymorphs, the danger exists of less soluble polymorphic forms precipitating from a solution made from another more soluble but less stable form. The formation of crystals in an ophthalmic solution can cause serious injury to the eye. In addition, precipitation of the drug substance may cause an apparent reduction in potency and bioavailability of the product. Therefore it is important to formulate ocular solutions with drug concentrations below the equilibrium solubility of the thermodynamically most stable polymorph of the drug.
A salt form of a prostaglandin may exhibit desirable solid state properties, such as high melting temperature and high crystallinity. Such properties may be advantageous with respect to manufacturing, stability, and/or solubility. Such a salt form may tolerate solid dosage formulation processes such as granulation, tablet compression and hot melt extrusion.
There is a need for solid state prostaglandins, in particular bimatoprost, with desirable physical properties, including high melting temperature and high crystallinity, which may provide suitable stability, solubility, and tolerability to solid dosage formulation processes.